The sensations of hunger and satiety are mediated through communication between the gastrointestinal system and the brain. Duraffourd et al. found that μ-opioid receptor (MOR)–1 was present in the nerves associated with the portal vein that collects blood from the gut. Peptide products of protein digestion can function either as agonists (β1-7 casomorphin) or antagonists (casoxin C) of MORs. Rats infused in the mesenteric vein with agonists of MOR exhibited decreased glucose-6 phosphatase (G6Pase) activity and increased food intake, whereas those infused with MOR antagonists exhibited increased G6Pase activity and intestinal glucose production, stimulation of neuronal activity in the dorsal vagal complex and hypothalamic regions of the brain involved in sensing hunger and satiety, and reduced food intake. The abundance of enzymes involved in gluconeogenesis and G6Pase activity was increased in the guts of rats fed a protein-enriched diet (either from animal protein or plant protein), and these increases were reversed by infusion of MOR agonists. Infusion of the dipeptides Tyr-Ala or Gly-Gly stimulated intestinal gluconeogenesis and G6Pase activity. In a cultured neuroblastoma cell line, each of these two dipeptides competed for binding with a pharmacological MOR agonist, consistent with these dipeptides functioning as protein product antagonists of MOR. The effects of MOR agonists and antagonists on brain neuronal activity, feeding, and intestinal gluconeogenesis and G6Pase activity were lost if portal vein innervation was destroyed with capsaicin. MOR-knockout mice or mice with an intestine-specific loss of G6Pase activity failed to respond to infusion of MOR agonists or antagonists. Switching MOR-knockout mice from a starch-enriched diet to a protein-enriched diet failed to result in reduced food intake as observed for wild-type mice. Thus, it appears that intestinal digestion of protein produces peptides that inhibit MOR signaling and thus trigger intestinal gluconeogenesis and brain circuits involved in satiety.